Kidney injury disorders, including primary nephropathy and secondary nephropathy such as diabetic nephropathy and renal inadequacy are clinically manifested as heavy proteinuria, which, if not treated timely, would results in the kidney failure.
There are many inducing causes for kidney injury, including the common diseases such as diabetes and hypertension, which can result in kidney injury. For example, 15%-25% of patients having Type I diabetes and 30%-40% of patients having Type II diabetes have the diabetic nephropathy, which has became the primary etiology in the end-stage nephropathy (accounting for 40%). For treating kidney injury, there is not any effective therapeutic medicine now.
Aldosterone is a mineralocorticoid synthesized in the adrenal cortex and distributes in several tissues including kidney, colon, epithelial cell of sweat glands, blood vessel, brain, and cardiac muscle. It activates a mineralocorticoid receptor by combining with its receptor, so as to promote the sodium retention and the potassium secretion and have important effects on the electrolyte balance and the change in structure and function of endothelial cell on arterial wall, vascular smooth muscle cell, fibroblast, and tunica adventitia of artery and the matrix on its medium.
The extra high level of aldosterone results in the abnormal activation of the mineralocorticoid receptor. This causes the electrolyte imbalance and the injury and filtration of blood vessel of kidney, resulting in kidney injury, hypertension and the like.
Drugs block the combination of aldosterone and the mineralocorticoid receptor by competitively combining with the mineralocorticoid receptor, so at to inhibit the toxic effect mediated by aldosterone and reduce kidney injury. There are two commercially available drugs in the market: Spironolactone and Eplerenone, which are indicated to treat hypertension, heart failure, renal syndrome and the like. These two drugs belong to the steroid class compound, have poor selectivity over other steroid hormone receptor, and are liable to the cause of hyperkaliemia and other major side effects. Furthermore, these two drugs have complicated structures and therefore are difficult to be synthesized. In addition, these two drugs have poor physical/chemical properties that limit their clinical use.
A non-steroid compound (as shown in formula V) mentioned in the patent application CN200780043333.0 has entered the clinical stage I, has a better performance in the preclinical pharmaceutical effect and safety than the listed drugs, and has effects in reducing proteinuria and reducing kidney injury.

However, the compound has poor cellular activity and sub-optimal physical chemical properties. In order to improve the clinical efficacy and safe clinical administration, it is in need to develop a novel non-steroid class compound that has good activity, synthetically feasible, and has good physical and chemical properties.